The goal of this project is to enhance the efficacy of T depleted haplocompatible parental marrow grafts in reconstituting hematopoietic stem cells (HSC) and inducing tolerance without graft vs. host disease (GVHD) in children with inborn errors of metabolism, marrow stem cell defects or leukemia. We will focus on: 1) fetuses diagnosed early in gestation with a marrow stem cell defect or inborn error of metabolism, 2) infants with severe combined immunodeficiency disease and 3) children with leukemia. The specific aims are: 1) to assess the efficacy of T depleted haplocompatible parental bone marrow in engrafting HSC in fetuses with hemoglobinopathies or SCID; 2) to assess the development of tolerance following transplantation of T depleted haplocompatible marrow and the role that monocytes play in tolerance induction; and 3) to define the sequence of T cell, B cell and monocyte reconstitution following haplocompatible T cell depleted BMT, and investigate the ability of engrafted donor T cells to collaborate with host/donor B cells and antigen presenting cells for the induction of specific antibody production. We will utilize prenatal diagnosis and processed parental marrow to evaluate the potential for inducing tolerance to allogenic HSC in utero. We will also evaluate mechanisms of tolerance in these transplants, as well as engraftment of haplocompatible marrow in children with SCID or leukemia, and understand why the recovery of B cell function and, in some cases T cell immunity is so delayed. These studies will result in a broader application of these techniques to the treatment of a variety of congenital diseases and malignancies.